Research ArticleNeurodegeneration

Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease

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Science Signaling  10 May 2016:
Vol. 9, Issue 427, pp. ra47
DOI: 10.1126/scisignal.aaf6209

PKCα variants in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by neurodegeneration and impaired neuronal function in the brain that lead to progressive cognitive loss. The early-onset form of AD is linked to genetic mutations, and accumulation of a protein called amyloid-β occurs in many patients with both early- and late-onset AD. By examining the genetics of a large cohort of families in which late-onset AD was diagnosed, Alfonso et al. found that activating mutations in protein kinase Cα (PKCα) correlated with the disease. Pharmacologically inhibiting PKCα or deleting the gene encoding it prevented amyloid-β from impairing synaptic activity in hippocampal tissue slices from mice. This study suggests that PKCα variants mediate the pathological effects of amyloid-β in some patients with late-onset AD.


Alzheimer’s disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-β (Aβ) accumulation in the brain. Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), we identified three highly penetrant variants in PRKCA, the gene that encodes protein kinase Cα (PKCα), in five of the families. All three variants linked with LOAD displayed increased catalytic activity relative to wild-type PKCα as assessed in live-cell imaging experiments using a genetically encoded PKC activity reporter. Deleting PRKCA in mice or adding PKC antagonists to mouse hippocampal slices infected with a virus expressing the Aβ precursor CT100 revealed that PKCα was required for the reduced synaptic activity caused by Aβ. In PRKCA−/− neurons expressing CT100, introduction of PKCα, but not PKCα lacking a PDZ interaction moiety, rescued synaptic depression, suggesting that a scaffolding interaction bringing PKCα to the synapse is required for its mediation of the effects of Aβ. Thus, enhanced PKCα activity may contribute to AD, possibly by mediating the actions of Aβ on synapses. In contrast, reduced PKCα activity is implicated in cancer. Hence, these findings reinforce the importance of maintaining a careful balance in the activity of this enzyme.

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